Alcohol has long been associated with anti-inflammation and immunosuppression. The molecular mechanisms underlying these effects are not fully defined. In the preliminary studies, we performed whole-genome high-density microarray analyses on human airway epithelia exposed to varied doses of alcohol. A cluster of alcohol-responsive genes was identified. Among them, glucocorticoid-induced leucine zipper (GILZ), a prominent glucocorticoid (GC) target gene, responded to alcohol in a dose-dependent manner. GILZ is a major mediator to transduce glucosteroid actions in cells. This novel finding reveals a potentially important signaling pathway which may contribute to the alcohol-associated anti-inflammation and immunosuppression. The ultimate goal of this application is to define alcohol-specific GILZ regulatory network at the system level. There are three specific aims: 1) Specific Aim 1: To identify the trans-acting factors which bind to the GILZ gene promoter and are responsible for alcohol-mediated activation of GILZ; Specific Aim 2: To examine GILZ chromosomal occupancy induced by alcohol by chromatin immunoprecipitation sequencing (ChIP-seq) to profile the GILZ-targeting sequences across the genome and to delineate the alcohol-specific GILZ molecular network; 3) Specific Aim 3: To define the GILZ role in inflammatory cytokine response to LPS in multiple types of cells under alcohol exposure. The proposed research will allow us to test the central hypothesis that the alcohol-induced GILZ upregulation contributes to alcohol anti- inflammation and immunosuppression through a specific regulatory network. By completion of this proposal, we will gain the groundbreaking knowledge to help understand how alcohol acts like steroids to modulate cellular functions molecularly. This research will provide new insights into the mechanism of alcohol-induced anti-inflammation and immunosuppression, which may lead to rational design of therapeutics for the treatment of alcohol-associated diseases.